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Dive into the research topics where Scott L. Carter is active.

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Featured researches published by Scott L. Carter.


Nature | 2013

Mutational heterogeneity in cancer and the search for new cancer-associated genes.

Michael S. Lawrence; Petar Stojanov; Paz Polak; Gregory V. Kryukov; Kristian Cibulskis; Andrey Sivachenko; Scott L. Carter; Chip Stewart; Craig H. Mermel; Steven A. Roberts; Adam Kiezun; Peter S. Hammerman; Aaron McKenna; Yotam Drier; Lihua Zou; Alex H. Ramos; Trevor J. Pugh; Nicolas Stransky; Elena Helman; Jaegil Kim; Carrie Sougnez; Lauren Ambrogio; Elizabeth Nickerson; Erica Shefler; Maria L. Cortes; Daniel Auclair; Gordon Saksena; Douglas Voet; Michael S. Noble; Daniel DiCara

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour–normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.


Science | 2011

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Nicolas Stransky; Ann Marie Egloff; Aaron D. Tward; Aleksandar D. Kostic; Kristian Cibulskis; Andrey Sivachenko; Gregory V. Kryukov; Michael S. Lawrence; Carrie Sougnez; Aaron McKenna; Erica Shefler; Alex H. Ramos; Petar Stojanov; Scott L. Carter; Douglas Voet; Maria L. Cortes; Daniel Auclair; Michael F. Berger; Gordon Saksena; Candace Guiducci; Robert C. Onofrio; Melissa Parkin; Marjorie Romkes; Joel L. Weissfeld; Raja R. Seethala; Lin Wang; Claudia Rangel-Escareño; Juan Carlos Fernández-López; Alfredo Hidalgo-Miranda; Jorge Melendez-Zajgla

The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies. Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.


Nature Biotechnology | 2013

Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.

Kristian Cibulskis; Michael S. Lawrence; Scott L. Carter; Andrey Sivachenko; David M Jaffe; Carrie Sougnez; Stacey Gabriel; Matthew Meyerson; Eric S. Lander; Gad Getz

Detection of somatic point substitutions is a key step in characterizing the cancer genome. However, existing methods typically miss low-allelic-fraction mutations that occur in only a subset of the sequenced cells owing to either tumor heterogeneity or contamination by normal cells. Here we present MuTect, a method that applies a Bayesian classifier to detect somatic mutations with very low allele fractions, requiring only a few supporting reads, followed by carefully tuned filters that ensure high specificity. We also describe benchmarking approaches that use real, rather than simulated, sequencing data to evaluate the sensitivity and specificity as a function of sequencing depth, base quality and allelic fraction. Compared with other methods, MuTect has higher sensitivity with similar specificity, especially for mutations with allelic fractions as low as 0.1 and below, making MuTect particularly useful for studying cancer subclones and their evolution in standard exome and genome sequencing data.


Nature | 2011

The genomic complexity of primary human prostate cancer

Michael F. Berger; Michael S. Lawrence; Francesca Demichelis; Yotam Drier; Kristian Cibulskis; Andrey Sivachenko; Andrea Sboner; Raquel Esgueva; Dorothee Pflueger; Carrie Sougnez; Robert C. Onofrio; Scott L. Carter; Kyung Park; Lukas Habegger; Lauren Ambrogio; Timothy Fennell; Melissa Parkin; Gordon Saksena; Douglas Voet; Alex H. Ramos; Trevor J. Pugh; Jane Wilkinson; Sheila Fisher; Wendy Winckler; Scott Mahan; Kristin Ardlie; Jennifer Baldwin; Jonathan W. Simons; Naoki Kitabayashi; Theresa Y. MacDonald

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, ‘copy-neutral’) rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2–ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.


Nature Genetics | 2012

Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

Christopher E. Barbieri; Sylvan C. Baca; Michael S. Lawrence; Francesca Demichelis; Mirjam Blattner; Jean Philippe Theurillat; Thomas A. White; Petar Stojanov; Eliezer M. Van Allen; Nicolas Stransky; Elizabeth Nickerson; Sung Suk Chae; Gunther Boysen; Daniel Auclair; Robert C. Onofrio; Kyung Park; Naoki Kitabayashi; Theresa Y. MacDonald; Karen Sheikh; Terry Vuong; Candace Guiducci; Kristian Cibulskis; Andrey Sivachenko; Scott L. Carter; Gordon Saksena; Douglas Voet; Wasay M. Hussain; Alex H. Ramos; Wendy Winckler; Michelle C. Redman

Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6–15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.


Cell | 2013

Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Dan A. Landau; Scott L. Carter; Petar Stojanov; Aaron McKenna; Kristen E. Stevenson; Michael S. Lawrence; Carrie Sougnez; Chip Stewart; Andrey Sivachenko; Lili Wang; Youzhong Wan; Wandi Zhang; Sachet A. Shukla; Alexander R. Vartanov; Stacey M. Fernandes; Gordon Saksena; Kristian Cibulskis; Bethany Tesar; Stacey Gabriel; Nir Hacohen; Matthew Meyerson; Eric S. Lander; Donna Neuberg; Jennifer R. Brown; Gad Getz; Catherine J. Wu

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.


Nature | 2012

Sequence analysis of mutations and translocations across breast cancer subtypes

Shantanu Banerji; Kristian Cibulskis; Claudia Rangel-Escareño; Kristin K. Brown; Scott L. Carter; Abbie M. Frederick; Michael S. Lawrence; Andrey Sivachenko; Carrie Sougnez; Lihua Zou; Maria L. Cortes; Juan Carlos Fernández-López; Shouyong Peng; Kristin Ardlie; Daniel Auclair; Verónica Bautista-Piña; Fujiko Duke; Joshua M. Francis; Joonil Jung; Antonio Maffuz-Aziz; Robert C. Onofrio; Melissa Parkin; Nam H. Pho; Valeria Quintanar-Jurado; Alex H. Ramos; Rosa Rebollar-Vega; Sergio Rodriguez-Cuevas; Sandra Romero-Cordoba; Steven E. Schumacher; Nicolas Stransky

Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3–AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.


Nature Genetics | 2013

Pan-cancer patterns of somatic copy number alteration

Travis I. Zack; Steven E. Schumacher; Scott L. Carter; Andrew D. Cherniack; Gordon Saksena; Barbara Tabak; Michael S. Lawrence; Cheng-Zhong Zhang; Jeremiah Wala; Craig H. Mermel; Carrie Sougnez; Stacey Gabriel; Bryan Hernandez; Hui Shen; Peter W. Laird; Gad Getz; Matthew Meyerson; Rameen Beroukhim

Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting related functions. These results provide insights into mechanisms of generation and functional consequences of cancer-related SCNAs.


Nature Genetics | 2006

A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers

Scott L. Carter; Aron Charles Eklund; Isaac S. Kohane; Lyndsay Harris; Zoltan Szallasi

We developed a computational method to characterize aneuploidy in tumor samples based on coordinated aberrations in expression of genes localized to each chromosomal region. We summarized the total level of chromosomal aberration in a given tumor in a univariate measure termed total functional aneuploidy. We identified a signature of chromosomal instability from specific genes whose expression was consistently correlated with total functional aneuploidy in several cancer types. Net overexpression of this signature was predictive of poor clinical outcome in 12 cancer data sets representing six cancer types. Also, the signature of chromosomal instability was higher in metastasis samples than in primary tumors and was able to stratify grade 1 and grade 2 breast tumors according to clinical outcome. These results provide a means to assess the potential role of chromosomal instability in determining malignant potential over a broad range of tumors.


Nature Biotechnology | 2012

Absolute quantification of somatic DNA alterations in human cancer

Scott L. Carter; Kristian Cibulskis; Elena Helman; Aaron McKenna; Hui Shen; Travis I. Zack; Peter W. Laird; Robert C. Onofrio; Wendy Winckler; Barbara A. Weir; Rameen Beroukhim; David Pellman; Douglas A. Levine; Eric S. Lander; Matthew Meyerson; Gad Getz

We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.

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Aaron McKenna

University of Washington

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